Use of 1-benzyl-aminoalkyl-pyrrolidinones as antidepressants

ABSTRACT

The invention relates to the use of 1-benzyl-aminoalkyl-pyrrolidinones as antidepressants.

The invention relates to the use of 1-benzyl-aminoalkyl-pyrrolidinonesof general formula ##STR1## wherein R₁ represents hydrogen or an alkylgroup, R₂ represents a phenyl group which may be mono- or disubstitutedby alkoxy, fluorine, chlorine, bromine, trifluoromethyl, alkyl, hydroxyor nitro, or R₂ represents a pyridyl group, R₃ represents hydrogen or analkyl group and R₄ may represent hydrogen or an alkyl group or the twogroups R₃ and R₄ together with the nitrogen atom may represent asaturated 5- or 6-membered ring which may contain an O or N atom as afurther heteroatom and may optionally be substituted by methyl or theymay form an imidazole ring, wherein the aminoalkyl group is in the 4 or5 position, and the pharmacologically acceptable acid addition saltsthereof, as antidepressants.

In general formula I the term "alkyl" indicates a straight chained orbranched alkyl group with 1 to 4 carbon atoms such as, for example,methyl, ethyl, propyl, isopropyl, n-butyl or tert.-butyl and the term"alkoxy" indicates a group with 1 to 2 carbon atoms; the pyridyl ringgiven as a definition of R₂ may be linked to the methylene bridge in the2, 3 or 4 position. Methyl and ethyl are the preferred alkyl groups.

Compounds of general formula I and processes for preparing them areknown from European Patent Application No. 136 658, which discloses theefficacy of the compounds in cases of restricted cerebral performance.

Surprisingly, it has been found that the compounds of general formula Iare highly effective antidepressants of a new structural type.

Preferred compounds are the compounds of general formula I wherein R₁represents hydrogen, R₂ represents a phenyl group optionally substitutedby fluorine, chlorine, methyl or methoxy in the o or p position and R₃and R₄ represent hydrogen or methyl or R₃ and R₄ together representmorpholine or N-methylpiperazine.

Other suitable compounds include:

1-(3,4-Dimethoxybenzyl)-4-aminomethyl-pyrrolidin-2-one

1-(4-Methylbenzyl)-4-aminomethyl-pyrrolidin-2-one

1-(3-Trifluoromethylbenzyl)-4-aminomethyl-pyrrolidin-2-one

1-(α-Methylbenzyl)-4-aminomethyl-pyrrolidin-2-one

1-Benzyl-4-piperidinomethyl-pyrrolidin-2-one

1-Benzyl-4-(N-methylpiperazinomethyl)-pyrrolidin-2-one

1-Benzyl-4-(imidazo-1-yl-methyl)-pyrrolidin-2-one

1-Benzyl-4-methylaminomethyl-pyrrolidin-2-one

1-(p-Fluorobenzyl)-4-dimethylaminomethyl-pyrrolidin-2-one

1-(4-Nitrobenzyl)-4-aminomethyl-pyrrolidin-2-one

1-(4-Hydroxybenzyl)-4-aminomethyl-pyrrolidin-2-one

1-(o-Chlorobenzyl)-4-aminomethyl-pyrrolidin-2-one

1-(o-Chlorobenzyl)-4-diethylaminomethyl-pyrrolidin-2-one

1-Benzyl-4-isopropylaminomethyl-pyrrolidin-2-one

1-(p-Methylbenzyl)-4-diethylaminomethyl-pyrrolidin-2-one

1-Benzyl-5-dimethylaminomethyl-pyrrolidin-2-one

1-Benzyl-5-morpholinomethyl-pyrrolidin-2-one

1-Benzyl-5-(4-methylpiperazino)-methyl-pyrrolidin-2-one

1-(4-Methylbenzyl)-5-dimethylaminomethyl-pyrrolidin-2-one

1-(4-Methylbenzyl-5-diethylaminomethyl-pyrrolidin-2-one

1-(p-Chlorobenzyl)-5-diethylaminomethyl-pyrrolidin-2-one

1-(3,4-Dichlorobenzyl)-5-dimethylaminomethyl-pyrrolidin-2-one

1-(3,4-Dichlorobenzyl)-5-diethylaminomethyl-pyrrolidin-2-one

1-(p-Methoxybenzyl-5-dimethylaminomethyl-pyrrolidin-2-one

1-(p-Methoxybenzyl)-5-diethylaminomethyl-pyrrolidin-2-one and

1-Benzyl-5-aminomethyl-pyrrolidin-2-one.

Preferred compounds are:

1-(4-Methoxybenzyl)-4-aminomethyl-pyrrolidin-2-one

1-Benzyl-4-N,N-diethylaminomethyl-pyrrolidin-2-one

1-(4-Fluorobenzyl)-4-aminomethyl-pyrrolidin-2-one

1-(4-Chlorobenzyl)-4-aminomethyl-pyrrolidin-2-one

1-(4-Pyridylmethyl)-4-aminomethyl-pyrrolidin-2-one

1-(4-Fluorobenzyl)-4-(morpholinomethyl)-pyrrolidin-2-one

1-Benzyl-4-(N-methylpiperazinylmethyl)-pyrrolidin-2-one and

1-Benzyl-4-methylaminomethyl-pyrrolidin-2-one.

Particularly preferred compounds are:

1-Benzyl-4-aminomethyl-pyrrolidin-2-one

1-Benzyl-5-pyrrolidinomethyl-pyrrolidin-2-one

1-Benzyl-5-diethylaminomethyl-pyrrolidin-2-one and

1-(p-chlorobenzyl)-5-dimethylaminomethyl-pyrrolidin-2-one.

A sensitive test for preclinical demonstration of antidepressantproperties is the chick call test. The call frequency of isolatedone-day-old chicks which decreases during the course of the test istaken as an experimental behavioural model for manifestations ofresignation in depression. The method was validated by testing numerousneurotropically active substances; it is characterised by highlyreproducible selectivity for antidepressants which are alreadyclinically tried and tested and which are capable of reactivating thelowered call rate, as a function of dosage (distress call activation inisolated chicks; A new behavioural model for antidepressants, E. Lehr,Psychopharmacol. 89. 21 (1986); Activierung des Kontaktrufens alstierexperimentelles Verhaltensmodell zur Depressionsforschung,[Activation of contact calling as an experimental behavioural model forresearching depression], E. Lehr, Fortschr. Neurol. Psychiat. 54, 26(1986).

Table I gives the pharmacological data for1-benzyl-4-aminomethyl-pyrrolidin-2-one (fumarate) [Compound A]. Bycomparison the corresponding values for 1-acetamido-2-pyrrolidinone[Compound B], a structurally similar nootropic, are also given.

                  TABLE 1                                                         ______________________________________                                                      Compound A Compound B                                           ______________________________________                                        Chick call test 40           >>160                                            ED.sub.150, mg/kg i.p.                                                        Tetrabenazine   110          >>640                                            antagonism                                                                    (ptosis alleviation,                                                          mouse)                                                                        LD.sub.50, mouse                                                                              >>2000                                                        mg/kg by oral route                                                           Effect on cholinergic                                                                         Demand       none                                             function                                                                      Receptor bonding                                                                              none         none                                             (adrenergic, seroto-                                                          nergic)                                                                       IC.sub.50 [10.sup.-9 mol/ltr]                                                                 >10 000                                                       ______________________________________                                    

Table II gives the pharmacological data of the above mentioned chickcall test of some compounds of the invention.

                  TABLE II                                                        ______________________________________                                         ##STR2##                      I                                                                           Chick                                                                         call                                                                          test                                                                          ED.sub.150                                                                    i.p.                                                             R.sub.2      mg/kg                                            ______________________________________                                            R(4-position)                                                             C   CH.sub.2NH.sub.2                                                                                 ##STR3##      25                                       D   CH.sub.2NH.sub.2                                                                                 ##STR4##      20                                       E   CH.sub.2NH.sub.2                                                                                 ##STR5##      100                                      F   CH.sub.2NH.sub.2                                                                                 ##STR6##      10                                            ##STR7##                                                                                        ##STR8##      80                                       H                                                                                  ##STR9##                                                                                        ##STR10##     18                                           R(5-position)                                                             J    CH.sub.2N(C.sub.2 H.sub.5).sub.2                                                                ##STR11##     0.01                                     K                                                                                  ##STR12##                                                                                       ##STR13##     0.1                                      L   CH.sub.2N(CH.sub.3).sub.2                                                                        ##STR14##     0.1                                      ______________________________________                                    

On the basis of the data shown, there is clear evidence of preclinicallyantidepressant properties, whilst the compounds according to theinvention do not show the typical side effects of conventionalantidepressants, such as sedation. The absence of receptor bondingproperties and/or inhibition of resorption of biogenic amines indicatesa completely new mechanism of activity for compounds with anantidepressant effect. The cholinomimetic property of the compounds ofgeneral formula I rules out any cardiotoxicity, which is caused inconventional antidepressants by their anticholinergic side effects andis one of the most serious undesirable drawbacks of such drugs. Owing tothe cholinergic property of the compounds of general formula I it ispossible to use the compounds in cases of depression even in geriatricpatients in whom, owing to their cholinergic malfunction, conventionalantidepressants are contra-indicated on account of their anticholinergicside effects.

Processes for preparing compounds of general formula I and thepharmacologically acceptable acid addition salts thereof are describedin European Patent Application No. 136 658, the contents of which arereferred to here.

The compounds of general formula I may be used on their own or inconjunction with other active substances according to the invention, andpossibly in conjunction with other pharmacologically active substances.Suitable forms for administration include tablets, capsules,suppositories, solutions, syrups, emulsions and dispersible powders.Tablets may be produced, for example, by mixing the active substance orsubstances with known excipients, e.g. inert diluents such as calciumcarbonate, calcium phosphate or lactose, disintegrants such as cornstarch or alginic acid, binders such as starch or gelatine, lubricantssuch as magnesium stearate or talc and/or agents for obtaining delayedrelease, such as carboxypolymethylene, carboxymethylcellulose, celluloseacetate phthalate or polyvinyl acetate. The tablets may also consist ofseveral layers.

Coated tablets may be prepared in the same way by coating cores producedanalogously to the tablets with subtances conventionally used for tabletcoatings, e.g. collidone or shellack, gum arabic, talc, titanium dioxideor sugar. In order to obtain delayed release or avoid intolerance, thecore may also consist of several layers. Similarly, the tablet coatingmay also consist of several layers in order to obtain delayed release,and the excipients mentioned for the tablets may be used.

Syrups containing the active substances or combinations of activesubstances according to the invention may additionally contain asweetener such as saccharin, cyclamate, glycerol or sugar and aflavour-enhancing agent, e.g. a flavouring such as vanillin or orangeextract. They may also contain suspension adjuvants or thickeners suchas sodium carboxymethylcellulose, wetting agents, e.g. condensationproducts of fatty alcohols with ethylene oxide, or preservatives such ap-hydroxybenzoates.

Injection solutions are produced in the usual way, e.g. by addingpreservatives such as p-hydroxybenzoates or stabilisers such as alkalimetal salts or ethylene diamine tetraacetic acid and the solutions aretransferred into injection vials of ampoules.

Capsules containing one or more active substances or combinations ofactive substances may be produced, for example, by mixing the activesubstances with inert carriers such as lactose or sorbitol and sealingthe mixture in gelatine capsules. Suitable suppositories may beproduced, for example, by mixing with the carriers provided for thispurpose, such as neutral fats or polyethylene glycol or the derivativesthereof.

The therapeutically effective dosage is generally from 1 to 150 mg,preferably from 50 to 100 mg for each single dose.

The Examples which follow illustrate the invention without restrictingits scope:

EXAMPLE 1 1-Benzyl-4-aminomethyl-pyrrolidin-2-one

54 g (0.16 mol) of 4-phthalimidomethyl-1-benzyl-pyrrolidin-2-one arestirred into 1.3 liters of ethyl alcohol after the addition of 32 g ofhydrazine hydrate for 4 hours at ambient temperature. The precipitate(phthalic acid hydrazide) is suction filtered and the filtrate isconcentrated by evaporation. 500 ml of methylene chloride are added tothe residue and it is extracted three times with 100 ml of water. Theorganic phase is dried and evaporated. The residue remaining isdissolved in 500 ml of methanol and 20 g (0.17 mol) of solid fumaricacid are added in batches at boiling temperature with stirring. When themixture cools, colourless crystals are precipitated which are suctionfiltered and then washed with methanol and ether. Yield: 20-25 g (48-60%of theory), m.p. 209°-211° C.

The compound contains 1/2 mol of fumaric acid. The starting material isobtained as follows:

(a) 94 g (0.46 mol) of 1-benzyl-4-hydroxymethyl-pyrrolidin-2-one arestirred with 700 ml of methylene chloride and 40 ml (0.54 mol) ofthionylchloride for 25 hours while refluxing and the reaction mixture isthen neutralised with dilute ammonia whilst being cooled. Afterseparation, drying and evaporation, 85-90 g of a dark oil are leftbehind, which is used directly for further reaction.

(b) 43.5 g (0.195 mol) of crude1-benzyl-4-chloromethyl-pyrrolidin-2-one, 36 g (0.195 mol) ofphthalimide potassium and 700 ml of dimethylformamide are refluxed for 2hours. The reaction mixture is then evaporated in vacuo and the residueis taken up in methylene chloride. It is extracted several times withwater, the organic phase is dried and after chromatography on SiO₂ 45 g(70% of theory) of the phthalimido compound are obtained, m.p. 108°-109°C.

EXAMPLE 2 1-Benzyl-4-aminomethyl-pyrrolidin-2-one

(a) 58 g (0.29 mol) of 1-benzyl-4-nitrilo-pyrrolidin-2-one are dissolvedin methanol and catalytically hydrogenated with the addition of liquidammonia over Raney nickel. After the reaction solution has beenconcentrated by evaporation, it is dissolved in methanol, the residualcatalyst is filtered off and after the filtrate has been heated to about50° C. it is mixed with 17 g of fumaric acid. The fumaric acid brieflygoes into solution when stirred, then the crystallization of the1-benzyl-4-aminomethyl-pyrrolidin-2-one fumarate begins.

Yield: 68 g (=91% of theory); m.p. 192°-194° C.

(b) The nitrilo compound is obtained in a 96% yield in the form of anoil from the corresponding amide, m.p. 162°-166° C., by dehydrationusing POCl₃ in dimethylformamide at about 60° C.

EXAMPLE 3 Racemate cleaving of 1-Benzyl-4-aminomethyl-pyrrolidin-2-one

(a) 24.0 g (0.117 mol) of 1-benzyl-4-aminomethyl-pyrrolidin-2-one aredissolved in 200 ml of hot methanol and 17.6 g (0.117 mol) ofL(+)-tartaric acid are also dissolved in 200 ml of hot methanol. The twosolutions are combined and cooled to ambient temperature with stirring,whereupon the salt crystallizes out. The crystals are suction filteredwhile cold, washed with cold methanol and dried.

Yield: 18.0 g of 4-aminomethyl-1-benzyl-pyrrolidin-2-one tartrate, m.p.204°-206° C. (from methanol), α_(D) =+6.3° (c=1.0; water).

(b) In order to convert the tartrate into the base the tartrate isdissolved cold in 20 ml of water and 10 ml of concentrated sodiumhydroxide solution and extracted three times with methylene chloride,then the combined mehtylene chloride phases are dried over MgSO₄ and thesolvent is eliminated in vacuo. The(-)-4-aminomethyl-1-benzyl-pyrrolidin-2-one is obtained, α_(D) =-8.4°(c=1.0; water).

(c) The mother liquors obtained in the processing described in (a) areconcentrated by evaporation in vacuo. 38.0 g of the tartrate isobtained, which is taken up cold in 140 ml of water and 50 ml ofconcentrated sodium hydroxide solution and extracted three times withmethylene chloride. The combined methylene chloride phases are driedover MgSO₄ and the solvent is eliminated in vacuo. 19.3 g of base areobtained, which is converted into the corresponding tartrate withD-(-)-tartaric acid as described in (a). Yield: 19.0 g m.p. 204°-205° C.

(d) The conversion of the tartrate into the base is carried out asdescribed in (b). 5.7 g of (+)-4-aminomethyl-1-benzyl-pyrrolidin-2-oneare obtained with a rotation α_(D) =+8.4° (c=1.0; water).

EXAMPLE 4 (-)-1-Benzyl-4-dimethylaminomethyl-pyrrolidin-2-one

4.0 g (0.02 mol) of (-)-1-benzyl-4-aminomethyl-pyrrolidin-2-one and 5.4g of 85% formic acid are mixed with 4.8 ml of formalin solution andstirred overnight at 100° C. (oil bath). Then the excess acid isdistilled off in vacuo and the residue is taken up in water, madealkaline with concentrated sodium hydroxide solution and extracted threetimes with methylene chloride. The combined methylene chloride phasesare washed with water, dried over sodium sulphate, the solvent isconcentrated in vacuo and the residue is filtered over an SiO₂ column(eluant: methylene chloride:methanol=97:3). The uniform fraction isconcentrated by evaporation in vacuo. The title compound is obtained ina yield of 3.5 g (in the form of an oil). α_(D) =-7.6° (c=1.0; methanol)α_(D) =-16.8° (c=1.0; water).

Analogously to Example 4, 6.1 g of(+)-1-benzyl-4-dimethylaminomethyl-pyrrolidin-2-one are obtained, α_(D)=+7.9° (c=1.0; methanol), from 5.8 g (0.028 mol) of(+)-1-benzyl-4-aminomethyl-pyrrolidin-2-one 7.9 g of 85% formic acid and7 ml of formalin solution.

EXAMPLE 5 1-Benzyl-4-di-ethylaminomethyl-pyrrolidin-2-one

14 g (0.06 mol) of crude 1-benzyl-4-chloromethyl-pyrrolidin-2-one,prepared as in Example 1(a), 10 g of diethylamine and 50 ml ofdimethylformamide are stirred or shaken for 2 hours at 150° C. in theautoclave. The mixture is evaporated to dryness in vacuo and the residueis taken up in methylene chloride then washed first with water andfinally the title compound is extracted twice with 25 ml of 2 NHCl. Theaqueous phase is removed, made alkaline with sodium hydroxide solutionand the organic base is extracted with methylene chloride. The methylenechloride phase is concentrated by evaporation and the residue isdistilled in vacuo.

Yield: 10 g (61% of theory), bp₀.05 = 155°-158° C.

EXAMPLE 6 (-)-1-Benzyl-4-diethylaminomethyl-pyrrolidin-2-one

11.5 g (0.056 mol) of (-)-1-benzyl-4-aminomethyl-pyrrolidin-2-one, 130ml of water, 13 g of acetaldehyde, 5.8 ml of concentrated hydrochloricacid and 6.5 g of Pd C 20% are hydrogenated for 51/4 hours at 5 bar andat 25° C. The residue is evaporated, taken in 30 ml of water andextracted with methylene chloride. The aqueous hydrochloric acidsolution is made alkaline and also extracted with methylene chloride. Bydistillation in a bulbed tube, 11.2 g (76.4% of theory) of the titlecompound are obtained, α_(D) =-9.4 (c=1.0; methanol). Analogously toExample 6, by hydrogenating 8.4 g (0.041 mol) of(+)-1-benzyl-4-aminomethyl-pyrrolidin-2-one, 95 ml of water, 9.5acetaldehyde, 4.2 ml of concentrated hydrochloric acid and 4.7 g of Pd/C20%. (+)-1-benzyl-4-diethylaminomethyl-pyrrolidin-2-one is obtained,α_(D) =+9.4 (c=1.0; methanol).

EXAMPLE 71-(4-Fluoro-benzyl)-4-N-methylpiperazinylmethyl-pyrrolidin-2-one

(a) 24 g (0.11 mol) of1-(4-fluorobenzyl)-4-hydroxymethyl-pyrrolidin-2-one are refluxed with 10ml (0.14 mol) of thionyl chloride in 200 ml of methylene chloride firstof all for 10 hours and then, after the addition of another 10 ml ofthionyl chloride, for a further 6 hours. Whilst cooling with ice, theproduct is neutralised with ammonia and after the organic phase has beenseparated off it is dried and concentrated by evaporation. 23 g (92% oftheory) of a reddish-brown oil remain, which is used without any furtherpurification.

(b) 5 g (0.002 mol) of the above oil are refluxed for 1-2 hours with 4.4g (0.04 mol) of 1-methyl-piperazine in 30 ml of dimethylformamide. Thedimethylformamide is then substantially distilled off in vacuo, theresidue is taken up in methylene chloride and washed with water and thenthe organic phase is dried and evaporated again. The residue ischromatographed on SiO₂ with methylene chloride/methanol 95:5 as eluant.The main fraction is concentrated by evaporation and the residue (5 g)is dissolved in 30 ml of methanol. 2.8 g of fumaric acid are added tothis solution. 5.2 g (48% of theory) of the title compound areprecipitated in crystalline form as the fumarate.

M.p. 179°-180° C.

EXAMPLE 8 1-(4-Fluorobenzyl)-4-morpholinomethyl-pyrrolidin-2-one

(a) 8.9 g (0.04 mol) of1-(4-fluorobenzyl)-4-hydroxymethyl-pyrrolidin-2-one in 100 ml ofabsolute methylene chloride and 4.8 g of pyridine are mixed with 6.9 g(0.06 mol) of methanesulphonic acid chloride. The mixture is refluxedfor 2.5 hours then cooled and extracted with dilute ammonia and water.The organic phase is dried and concentrated by evaporation. 11 g (93% oftheory) of crude ester are obtained, m.p. 84°-86° C.

(b) 6.7 g (0.023 mol) of ester and 2.6 g (0.03 mol) of morpholine arerefluxed for 2 hours in 20 ml of dioxan. The solvent is evaporated offin vacuo and the residue is taken up in methylene chloride and extractedwith 50 ml of 2N hydrochloric acid. The aqueous extracts are madealkaline with ammonia and the oily base is extracted with methylenechloride. The methylene chloride phase is dried and concentrated byevaporation. The residue (4.2 g) is taken up in 30 ml of methanol and1.2 g of fumaric acid are added in the warm. After cooling, the fumarateof the title compound is precipitated in crystalline form.

Yield: 7 g=57% of theory of colourless crystals, m.p. 175°-176° C.

EXAMPLE 9 1-(4-Fluorobenzyl)-4-amino-pyrrolidin-2-one

(a) 4.0 g (0.013 mol) of mesyl ester, prepared according to Example 7,are refluxed for 30 minutes with 2.8 g (0.015 mol) of phthalimidepotassium in 50 ml of dimethylformamide. The mixture is concentrated byevaporation in vacuo and the residue is taken up in methylene chloride,washed with water, the organic phase is dried and again concentrated byevaporation. The residue is triturated with ether and yields 3.6 g (78%of theory) of light grey crystals, m.p. 124°-125° C.

(b) 3.5 g (0.1 mol) of the above phthalimide compound are stirred with5.5 g of hydrazine hydrate in 200 ml of alcohol for 4 hours at ambienttemperature. The mixture is worked up as described in Example 1. 2.5 g(89% of theory) of the fumarate of the title compound are obtained, m.p.214°-215° C.

The title compound may also be obtained by dissolving 5 g (16 mmol) ofmesyl ester (see Example 7) in 100 ml of dimethylformamide and, afterthe addition of 1.3 g of sodium azide, heating the mixture to 100° C.for 2 hours, hydrogenating the oil which is obtained in due course withRaney nickel in methanol and converting the base into the fumarate asdescribed above.

Yield: 4.2 g (90% of theory).

The following end products were also obtained analogously to theprocedure described in the above Examples:

    __________________________________________________________________________     ##STR15##                                                                    Example                                                                       No.  R          R.sub.1                                                                           R.sub.2    Mp. °C./Bp. °C.                  __________________________________________________________________________    10   NH.sub.2   H                                                                                  ##STR16## Mp. 215-216 (Fumarate)                         11   NH.sub.2   H                                                                                  ##STR17## Mp. 187-189 (Fumarate)                         12   NH.sub.2   H                                                                                  ##STR18## Mp. 225-226 (Fumarate)                         13   NH.sub.2   H                                                                                  ##STR19## Mp. 189-191 (Fumarate)                         14   NH.sub.2   H                                                                                  ##STR20## Mp. 168-169 (Fumarate)                         15   NH.sub.2   H                                                                                  ##STR21## Mp. 179-181 (Fumarate)                         16   NH.sub.2   CH.sub.3                                                                           ##STR22## Mp. 167-168 (Fumarate)                         17                                                                                  ##STR23## H                                                                                  ##STR24## Mp. 58-60 Bp..sub.0,05 180 (Base)              18                                                                                  ##STR25## H                                                                                  ##STR26## Mp. 190-192 (Fumarate)                         19                                                                                  ##STR27## H                                                                                  ##STR28## Bp..sub.0,05 230 (Base)                        20   HNCH.sub.3 H                                                                                  ##STR29## Bp..sub.0,05 180 (Base)                        21   NH.sub.2   H                                                                                  ##STR30## Mp. 179-180 (Fumarate)                         22                                                                                  ##STR31## H                                                                                  ##STR32## Bp..sub.0,05 156 (Base)                        23   NHCH(CH.sub.3).sub.2                                                                     H                                                                                  ##STR33## Bp..sub.0,05 175 (Base)                        24                                                                                  ##STR34## H                                                                                  ##STR35## Bp..sub.0,05 175 (Base)                        __________________________________________________________________________

EXAMPLE 25 1-Benzyl-5-dimethylaminomethyl-pyrrolidin-2-one

(a) A solution of 10.26 g (0.05 mol) of1-benzyl-5-hydroxymethyl-pyrrolidin-2-one (m.p. 76°-77° C.) and 5.6 g(0.055 mol) of triethylamine in 80 ml of methylene chloride is mixedwith 6.3 g (0.055 mol) of methanesulphonic acid chloride in 20 ml ofmethylene chloride. The reaction mixture is then refluxed for 1 hourand, after being cooled, extracted with water. The organic phase isdried over anhydrous sodium sulphate and then concentrated byevaporation in a rotary evaporator. 14.1 g (yellow oil) of crude1-benzyl-5-hydroxymethyl-pyrrolidin-2-one methanesulphonic acid ester isobtained, which is used in the next reaction step without any furtherpurification.

(b) 8.5 g (0.03 mol) of the mesylate obtained in (a) are heated to 150°C. for 3 hours with a solution of 10 g of dimethylamine in 60 ml ofdioxan in an autoclave. After cooling the reaction mixture isconcentrated to dryness in vacuo. The residue is dissolved in 2Nhydrochloric acid and extracted with ether. The acidic aqueous phase ismade alkaline with concentrated ammonia and extracted with methylenechloride. The methylene chloride solution is dried and concentrated byevaporation. The residue (6.5 g) is converted into the acid fumarate ofthe title compound with an equivalent amount of fumaric acid. Yield: 6.4g (61% of theory); m.p. 137°-138° C.

The following were also prepared analogously to Example 25:

    __________________________________________________________________________     ##STR36##                                                                    Example                                                                       No.  R          R.sub.1                                                                         R.sub.2    Mp. °C./Bp. °C.                    __________________________________________________________________________    26   N(C.sub.2 H.sub.5).sub.2                                                                 H                                                                                ##STR37## Mp. 163-164 (Hydrochloride)                      27                                                                                  ##STR38## H                                                                                ##STR39## Mp. 167-169 (Oxalate)                            28                                                                                  ##STR40## H                                                                                ##STR41## Mp. 258 (Dihydrochloride)                        29                                                                                  ##STR42## H                                                                                ##STR43## Mp. 188-190 (Hydrochloride)                      30   N(CH.sub.3).sub.2                                                                        H                                                                                ##STR44## Mp. 163-164 (Fumarate)                           31   N(C.sub.2 H.sub.5).sub.2                                                                 H                                                                                ##STR45## Mp. 152-153 (Hydrochloride)                      32   N(CH.sub.3).sub.2                                                                        H                                                                                ##STR46## Mp. 157-158 (Fumarate)                           33   N(C.sub.2 H.sub.5).sub.2                                                                 H                                                                                ##STR47## Mp. 149-151 (Hydrochloride)                      34   N(CH.sub.3).sub.2                                                                        H                                                                                ##STR48## Mp. 167-168 (Fumarate)                           35   N(C.sub.2 H.sub.5).sub.2                                                                 H                                                                                ##STR49## Mp. 159-161 (Hydrochloride)                      36   N(CH.sub.3).sub.2                                                                        H                                                                                ##STR50## Oil (Base)                                       37   N(C.sub.2 H.sub.5).sub.2                                                                 H                                                                                ##STR51## Oil (Base)                                       __________________________________________________________________________

EXAMPLE 38 1-Benzyl-5-aminomethyl-pyrrolidin-2-one

16.4 g (0.07 mol) of 1-benzyl-5-hydroxymethyl-pyrrolidin-2-onemethanesulphonic acid ester (see Example 25 (a)) are dissolved in 200 mlof dimethylformamide and stirred for 90 minutes at 100° C. after theaddition of 4.6 g (0.07 mol) of sodium azide. After evaporation,distributing between water and methylene chloride and working up of theorganic phase, 13.8 g (92% of theory) of oil are obtained, which can bereacted further in its crude form. It is dissolved in 200 ml of methanoland, after the addition of Raney nickel, hydrogenated at 20° C. and 5bar. After the catalyst has been removed by suction filtering and thefiltrate has been evaporated, 11 g (85% of theory) of oil are obtainedwhich when dissolved in methanol and after the addition of fumaric acidyields the desired hemifumarate of the title compound (m.p. 187°-188°C.).

Pharmaceutical formulation Examples

    ______________________________________                                        (A) Tablets       per tablet                                                  ______________________________________                                        Active substance  100         mg                                              Lactose (powdered)                                                                              140         mg                                              Corn starch       240         mg                                              Polyvinylpyrrolidone                                                                            15          mg                                              Magnesium stearate                                                                              5           mg                                                                500         mg                                              ______________________________________                                    

The finely ground active ingredient, lactose and part of the corn starchare mixed together. The mixture is screened and then moistened with asolution of polyvinylpyrrolidone in water, kneaded, granulated whilstmoist and then dried. The granulate, the remaining corn starch and themagnesium stearate are screened and mixed together. The mixture iscompressed to form tablets of suitable shape and size.

    ______________________________________                                        (B) Tablets          per tablet                                               ______________________________________                                        Active substance     80        mg                                             Corn starch          190       mg                                             Lactose              55        mg                                             Microcrystalline cellulose                                                                         35        mg                                             Polyvinylpyrrolidone 15        mg                                             Sodium carboxymethyl starch                                                                        23        mg                                             Magnesium stearate   2         mg                                                                  400       mg                                             ______________________________________                                    

The finely ground active substance, some of the corn starch, lactose,microcrystalline cellulose and polyvinylpyrrolidone are mixed together,the mixture is screened and processed with the remaining corn starch andwater to form a granulate which is dried and screened. The sodiumcarboxymethyl starch and the magnesium stearate are added and themixture is compressed to form tablets of suitable size.

    ______________________________________                                        (C) Ampoules                                                                  ______________________________________                                        1-Benzyl-4-aminomethyl-                                                                            50.0      mg                                             pyrrolidin-2-one fumarate                                                     Sodium chloride      10.0      mg                                             Doubly distilled water q.s. ad                                                                     1.0       ml                                             ______________________________________                                    

Method

The active substance and sodium chloride are dissolved in doublydistilled water and the solution is transferred into ampoules understerile conditions.

    ______________________________________                                        (D) Drops                                                                     ______________________________________                                        1-Benzyl-4-aminomethyl-                                                                          5.0         g                                              pyrrolidin-2-one fumarate                                                     methyl p-hydroxybenzoate                                                                         0.1         g                                              propyl p-hydroxybenzoate                                                                         0.1         g                                              demineralised water q.s. ad                                                                      100.0       ml                                             ______________________________________                                    

Method

The active substance and preservatives are dissolved in demineralisedwater and the solution is filtered and transferred into vials eachcontaining 100 ml.

What is claimed is:
 1. A method of treating depression which comprisesadministering, to a human host suffering from depression anantidepressive amount of a compound of the formula I ##STR52## whereinR₁ represents hydrogen or a C₂ -C₄ alkyl group,R₂ represents a phenylgroup which may be mono- or disubstituted by C₁ -C₂ alkoxy, fluorine,chlorine, bromine trifluoromethyl, C₁ -C₄ alkyl, hydroxy or nitro, or R₂represents a pyridyl group, and R₃ and R₄ together with the nitrogenatom represent a group of the formula ##STR53## wherein R₅ is H ormethyl, or a pharmaceutically acceptable acid addition salt thereof.